Depression has been hypothesized to increase breast cancer risk, with a few prospective studies with e10 years of follow-up suggesting a 2-4 times increased breast cancer risk among women with depression. Antidepressants (ADs) might mitigate hypothesized influences of depression on breast cancer risk through anti-inflammatory effects or may increase breast cancer risk through increasing circulating prolactin, especially for selective serotonin reuptake inhibitors (SSRIs). However, the proportion of SSRI users in the general population who will experience increased prolactin is unknown, and literature relating ADs to breast cancer risk provide inconsistent results. Surprisingly, previous studies have not jointly considered depression and AD use; prior studies of depression on breast cancer risk have not controlled for AD use, and vice versa. Additionally, the possibility that any increased risk associated with AD use might be due to the depression for which the AD is prescribed rather than the AD itself has not been fully explored. Additional questions regarding the impact of duration of each of these factors on breast cancer risk also remain. As a result, the relationships between depression, AD use and breast carcinogenesis remain poorly understood. Clarifying both the independent and joint effects of these exposures will provide critical information for the millions of women who are depressed and/or use ADs. We propose a prospective cohort study using data from the Nurses' Health Study (NHS) and NHS2 with the objective of investigating the complex associations potentially linking depression, AD use, and prolactin to breast cancer risk. Data on depression and AD use, as well as a range of known breast cancer risk factors, are available from 93,696 women (with 3,952 incident breast cancers) in NHS starting in 2000 and from 103,825 women in NHS2 (with 3,571 incident breast cancers) starting in 1993. Additionally, a subset of NHS and NHS2 participants (N=3,575 in NHS and N=1,549 in NHS2) have at least one prolactin measurement available for analysis. This unique resource will afford us excellent statistical power and substantial efficiencies in cos and time to address the following Specific Aims: 1. To evaluate whether depression increases risk of incident breast cancer independent of AD use; 2. To assess the effects of AD use on incident breast cancer risk; and 3. To determine the effects of AD use on circulating prolactin levels. This will be the first study to comprehensively evaluate the relationships between depression, AD use and breast cancer and to examine the effects of ADs on circulating prolactin levels in a large, population-based sample. This research will provide vital new information for clinicians and patients considering the risks and benefits of treatment for depression. Our results can fill key gaps in the knowledge base while providing the foundation for further study (e.g. relating changes in prolactin levels resulting from SSRI use to incident breast cancer).